Ppar alpha selective compounds for the treatment of dyslipidemia and other lipid disorders

ABSTRACT

A class of chromane and chromene compounds having the structure shown below and pharmaceutically acceptable salts thereof are useful as therapeutic compounds, particularly in the treatment and control of hyperlipidemia, hypercholesterolemia, dyslipidemia, and other lipid disorders, and in delaying the onset of or reducing the risk of conditions and sequelae that are associated with these diseases, such as atherosclerosis.

FIELD OF THE INVENTION

The instant invention is concerned with a class of chromane and chromenecompounds and pharmaceutically acceptable salts thereof which are usefulas therapeutic compounds, particularly in the treatment and control ofhyperlipidemia, hypercholesterolemia, dyslipidemia, and other lipiddisorders, and in delaying the onset of or reducing the risk ofconditions and sequelae that are associated with these diseases,including atherosclerosis and Type 2 diabetes mellitus, often referredto as non-insulin dependent diabetes (NIDDM).

BACKGROUND OF THE INVENTION

Disorders of lipid metabolism (dyslipidemias) include various conditionscharacterized by abnormal concentrations of one or more lipids (i.e.cholesterol and triglycerides), and/or apolipoproteins (i.e.,apolipoproteins A, B, C and E), and/or lipoproteins (i.e., themacromolecular complexes formed by the lipid and the apolipoprotein thatallow lipids to circulate in blood, such as Low Density Lipoproteins(LDL), Very Low Density Lipoproteins (VLDL) and Intermediate DensityLipoproteins (IDL)). Cholesterol is mostly carried in Low DensityLipoproteins (LDL), and this component is commonly known as the “bad”cholesterol because it has been shown that elevations in LDL-cholesterolcorrelate closely to the risk of coronary heart disease. A smallercomponent of cholesterol is carried in the High Density Lipoproteins(HDL) and is commonly known as the “good” cholesterol. In fact, it isknown that the primary function of HDL is to accept cholesteroldeposited in the arterial wall and to transport it back to the liver fordisposal through the intestine. Although it is desirable to lowerelevated levels of LDL cholesterol, it is also desirable to increaselevels of HDL cholesterol. Generally, it has been found that increasedlevels of HDL are associated with lower risk for coronary heart disease(CHD). See, for example, Gordon, et al., Am. J. Med., 62, 707-714(1977); Stampfer, et al., N. England J. Med., 325, 373-381 (1991); andKannel, et al., Ann. Internal Med., 90, 85-91 (1979). An example of anHDL raising agent is nicotinic acid, a drug with limited utility becausedoses that achieve HDL raising are associated with undesirable effects,such as flushing.

Dyslipidemias were originally classified by Fredrickson according to thecombination of alterations mentioned above. The Fredricksonclassification includes 6 phenotypes (i.e., I, IIa, IIb, III, IV and V)with the most common being the isolated hypercholesterolemia (or typeIIa) which is usually accompained by elevated concentrations of totaland LDL cholesterol. The initial treatment for hypercholesterolemia isoften to modify the diet to one low in fat and cholesterol, coupled withappropriate physical exercise, followed by drug therapy whenLDL-lowering goals are not met by diet and exercise alone

A second common form of dyslipidemia is the mixed or combinedhyperlipidemia or type IIb and III of the Fredrickson classification.This dyslipidemia is often prevalent in patients with type 2 diabetes,obesity and the metabolic syndrome. In this dyslipidemia there aremodest elevations of LDL-cholesterol, accompanied by more pronouncedelevations of small dense LDL-cholesterol particles, VLDL and/or IDL(i.e., triglyceride rich lipoproteins), and total triglycerides. Inaddition, concentrations of HDL are often low.

Peroxisome proliferators are a structurally diverse group of compoundsthat when administered to rodents elicit dramatic increases in the sizeand number of hepatic and renal peroxisomes, as well as concomitantincreases in the capacity of peroxisomes to metabolize fatty acids viaincreased expression of the enzymes of the beta-oxidation cycle.Compounds of this group include but are not limited to the fibrate classof lipid modulating drugs, herbicides, phthalate plasticizers and theglitazones, a class of compounds that has been under investigation forthe treatment of type 2 diabetes. Peroxisome proliferation is alsotriggered by dietary or physiological factors such as a high-fat dietand cold acclimatization.

Three sub-types of peroxisome proliferator activated receptor (PPAR)have been discovered and described; they are peroxisome proliferatoractivated receptor alpha (PPARα), peroxisome proliferator activatedreceptor gamma (PPARγ) and peroxisome proliferator activated receptordelta (PPARδ). PPARα is activated by a number of medium and long-chainfatty acids, and it is involved in stimulating β-oxidation of fattyacids. PPARα is also associated with the activity of fibrates and fattyacids in rodents and humans. Fibric acid derivatives such as clofibrate,fenofibrate, bezafibrate, ciprofibrate, beclofibrate and etofibrate, aswell as gemfibrozil, each of which are PPARα ligands and/or activators,produce a substantial reduction in plasma triglycerides as well as someincrease in HDL. The effects on LDL cholesterol are inconsistent andmight depend upon the compound and/or the dyslipidemic phenotype. Forthese reasons, this class of compounds has been primarily used to treathypertriglyceridemia (i.e, Fredrickson Type IV and V) and/or mixedhyperlipidemia.

The PPARγ receptor subtypes are involved in activating the program ofadipocyte differentiation and are not involved in stimulating peroxisomeproliferation in the liver. There are two known protein isoforms ofPPARγ:PPARγ1 and PPARγ2 which differ only in that PPARγ2 contains anadditional 28 amino acids present at the amino terminus. The DNAsequences for the human isotypes are described in Elbrecht, et al., BBRC224;431-437 (1996). In mice, PPARγ2 is expressed specifically in fatcells. Tontonoz et al., Cell 79: 1147-1156 (1994) provide evidence toshow that one physiological role of PPARγ2 is to induce adipocytedifferentiation. As with other members of the nuclear hormone receptorsuperfamily, PPARγ2 regulates the expression of genes throughinteraction with other proteins and binding to hormone responseelements, for example in the 5′ flanking regions of responsive genes. Anexample of a PPARγ2 responsive gene is the tissue-specific adipocyte P2gene. Although peroxisome proliferators, including the fibrates andfatty acids, activate the transcriptional activity of PPAR's, onlyprostaglandin J₂ derivatives have been identified as potential naturalligands of the PPARγ subtype, which also binds thiazolidinedioneantidiabetic agents with high affinity.

The human nuclear receptor gene PPARδ (hPPARδ) has been cloned from ahuman osteosarcoma cell cDNA library and is fully described in A.Schmidt et al., Molecular Endocrinology, 6:1634-1641 (1992). It shouldbe noted that PPARδ is also referred to in the literature as PPARβ andas NUC1, and each of these names refers to the same receptor; in Schmidtet al. the receptor is referred to as NUC1.

In WO96/01430, a human PPAR subtype, hNUC1B, is disclosed. The aminoacid sequence of hNUC1B differs from human PPARδ (referred to therein ashNUC1) by one amino acid, i.e., alanine at position 292. Based on invivo experiments described therein, the authors suggest that hNUC1Bprotein represses hPPARα and thyroid hormone receptor protein activity.

It has been disclosed in WO97/28149 that agonists of PPARδ are useful inraising HDL plasma levels. PPARδ agonists have recently been disclosedin U.S. Provisional Application Ser. No. 60/297,356 as having utility inthe treatment of various inflammatory diseases, such as rheumatoidarthritis. WO97/27857, 97/28115, 97/28137 and 97/27847 disclosecompounds that are useful as antidiabetic, antiobesity,anti-atherosclerosis and antihyperlipidemic agents, and which activatePPARs.

It is generally believed that glitazones exert their effects by bindingto the peroxisome proliferator activated receptor (PPAR) family ofreceptors, controlling certain transcription elements having to do withthe biological entities listed above. Glitazones arebenzyl-2,4-thiazolidinedione derivatives. See Hulin et al., CurrentPharm. Design (1996) 2, 85-102.

A number of glitazones that are PPAR agonists have been approved for usein the treatment of diabetes. These include troglitazone, rosiglitazoneand pioglitazone, all of which are primarily or exclusively PPARγagonists. Many of the newer PPAR agonists that are currently underdevelopment or are in clinical trials have dual PPARα and γ activity,such as KRP-297. The PPARα/γ agonists are expected to improve bothinsulin sensitivity and the lipid profile in patients having NIDDM.

Although glitazones have been beneficial in the treatment of NIDDM,there have been some serious adverse events associated with the use ofthe compounds, especially troglitazone, which was eventually withdrawn.The most serious adverse events have been liver toxicity, which resultedin a number of deaths. Because of the problems that have occurred withthe glitazones, researchers in a number of laboratories have beeninvestigating classes of PPAR agonists that do not contain1,3-thiazolidinedione moieties and therefore are not glitazones.

Compounds that are agonists of the various PPAR sub-types are expectedto be useful in the treatment of diseases and conditions that respond totreatment with PPAR agonists, regardless of whether the compounds areglitazones. These include dyslipidemia, diabetes, and relatedconditions. PPARα agonists improve the lipid profile and alleviatedyslipidemias by reducing elevated LDL levels, reducing elevatedtriglyceride levels, and increasing HDL levels. PPARγ agonists improveinsulin sensitivity, reducing the need for insulin secretagogues andinsulin injections in patients with NIDDM. The role of PPARδ is lesswell defined, but PPARδ also appears to help control hyperlipidemia andhyperglycemia in type 2 diabetic patients.

SUMMARY OF THE INVENTION

The class of compounds described herein is a new class of potent PPARαagonists that do not contain a 1,3-thiazolidinedione moiety. Theyexhibit little or no activity at the PPARγ and PPARδ receptor, and theyare therefore selective. Preferred compounds have a high affinity forthe PPARα receptor, with an IC₅₀ less than 250 nM, using the PPARαbinding assay. The compounds generally have an IC₅₀ greater than 15,000in the PPARγ binding assay, and greater than 50,000 in the PPARδ bindingassay. The compounds are useful in the treatment of diseases, disordersand conditions that are treated or ameliorated by PPARα agonists.

The compounds are useful in treating one or more of the followingconditions: mixed or diabetic dyslipidemia; other lipid disorders,including isolated hypercholesterolemia as manifested by elevations inLDL-C and/or non-HDL-C; hyperapoBliproteinemia; hypertriglyceridemia;elevated triglyceride-rich-lipoproteins; and low HDL cholesterolconcentrations. The compounds may also have utility in treating orameliorating atherosclerosis, obesity, vascular restenosis, andinflammatory conditions. As a result of their utility in treating andameliorating lipid disorders and obesity, and perhaps insulin resistanceand/or hyperglycemia, the compounds of this invention also may beeffective in treating or ameliorating the metabolic syndrome, also knownas Syndrome X. They may also reduce the risk of developingatherosclerosis in a patient at risk of developing atherosclerosis byameliorating some of the risk factors, such as those that are thecriteria that define metabolic syndrome.

The present invention provides compounds having the structure of FormulaI, including pharmaceutically acceptable salts and prodrugs of thesecompounds:

In the compounds of Formula I:

-   -   R¹ and R² are each C₁-C₃ alkyl, which are optionally substituted        with 1-5 halogens independently selected from F and Cl;    -   R³ is selected from the group consisting of        -   (a) H, and        -   (b) C₁-C₃alkyl, which is optionally substituted with 1-5            halogens independently selected from F and Cl;    -   R⁴ is C₁-C₃ alkyl, which is optionally substituted with 1-5        halogens independently selected from F and Cl;    -   R⁵ is selected from the group consisting of H and C₁-C₃alkyl,        which is optionally substituted with 1-5 halogens independently        selected from F and Cl;    -   R⁶ is selected from H, Cl, CH₃ and CF₃;    -   R⁷ is H or C₁-C₃ alkyl, which is optionally substituted with 1-5        halogens independently selected from F and Cl;

A and B are each independently selected from H, Cl, F, CH₃, and CF₃;

-   -   The dashed line connecting the ring carbon atoms attached to R⁵        and R⁷ is an optional double bond;    -   X and Y are each O or S; and    -   n is 2 or 3.

In the above summary, reference to alkyl groups by carbon number, suchas C₃ alkyl or C₃₋₆ alkyl, refers to linear or branched alkyl.

The compounds described above are effective in treating diseases orconditions that respond to treatment with PPARα agonists. The compoundsare expected to be efficacious in treating or ameliorating one or moreof the following diseases or conditions: hyperlipidemia, dyslipidemia,hypercholesterolemia, hypertrigyceridemia, and obesity. Some of thecompounds may also be efficacious in treating or amelioratingnon-insulin dependent diabetes mellitus (NIDDM) in mammalian patientsand human patients in need of treatment, and in the treatment andamelioration of conditions that are often associated with NIDDM, butwhich may also be present in non-diabetic patients, includinghyperlipidemia, dyslipidemia, hypercholesterolemia, hypertrigyceridemia,and obesity. The compounds may also be effective in treatingatherosclerosis, hyperinsulinemia, insulin resistance, vascularrestenosis, and inflammatory conditions. The compounds may delay orreduce the risk of one or more of the sequelae of NIDDM, such asatherosclerosis, vascular restenosis, and retinopathy by amelioratingsome of the conditions that contribute to the development of thesediseases. They may also be effective in reducing cardiovascular eventsthat occur in human patients having metabolic syndrome, such as coronaryheart disease.

DETAILED DESCRIPTION OF THE INVENTION

The invention has numerous embodiments. Several preferred sub-groups ofcompounds are described below:

One embodiment is the sub-group of compounds having Formula I, where Xand Y are each O.

Another embodiment is the sub-group of compounds having Formula I, whereA, B, and R⁷ are H.

Compounds of Formula I in which R⁵ is CF₃ comprise another preferredsub-group of compounds of this invention.

Compounds of Formula I in which R⁵ is C₁-C₃ alkyl are another preferredsub-group of compounds.

In another sub-group of compounds having Formula I, R⁶ is selected fromCl, CH₃ and CF₃. In many preferred compounds of this sub-group, R⁶ isCl.

In another embodiment of compounds having Formula I, R³ is H, CH₃, C₂H₅,or C₃H₇; and R4 is CH₃, C₂H₅, or C₃H₇. In a preferred sub-group, R3 andR4 are each selected from CH₃, C₂H₅, and C₃H₇.

In still another embodiment of compounds having Formula I, R¹ and R²each independently may be CH₃ or C₂H₅.

A preferred sub-group of compounds of Formula I comprises compounds inwhich R¹ and R² are each CH₃.

A preferred sub-set of compound having Formula I, includingpharmaceutically acceptable salts, is described as follows:

R¹ and R² are each independently CH₃ or C₂H₅;

R³ and R⁴ are each independently selected from CH₃, C₂H₅, and C₃H₇;

R⁵ is CF₃;

R⁶is Cl;

R⁷, A, and B are all H;

The dashed line connecting the ring carbon atoms that are attached to R⁵and R⁷ is a double bond;

X and Y are O; and

n is 2 or 3.

A preferred subgroup of the compounds described immediately abovecomprises compounds having Formula I in which R¹ and R² are each CH₃.

Another preferred subgroup comprises compounds in which n is 3.

Specific examples of compounds of this invention are provided inExamples 1-9. These compounds are illustrated in the Table of Compoundsimmediately before the Examples.

The invention further includes pharmaceutical compositions comprisingany of the compounds described herein, including pharmaceuticallyacceptable salts, and a pharmaceutically acceptable carrier.

Definitions

“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxyor alkenyl, means carbon chains which may be linear or branched,including chains with multiple branch points, unless the carbon chain isdefined otherwise. Examples of alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl,octyl, nonyl, and the like. Isopropyl and sec- and tert-butyl arebranched.

“Alkenyl” means carbon chains which contain at least one carbon-carbondouble bond, and which may be linear or branched. Examples of alkenylinclude vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl,1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.

“Cycloalkyl” means a mono- or bicyclic saturated carbocyclic ring havingfrom 3 to 10 carbon atoms, unless otherwise stated. The term alsoincludes a monocyclic or bicyclic saturated carbocyclic ring which isfused to another cyclic group, such as an aryl group. Examples ofcycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,and the like.

“Aryl” (and “arylene”) when used to describe a substituent or group in astructure means a monocyclic or bicyclic or tricyclic group orsubstituent in which all of the rings are aromatic and which containsonly carbon ring atoms. “Aryl” groups can be fused to other cyclicgroups, such as a cycloalkyl or heterocyclic group. Examples of arylsubstituents include phenyl and naphthyl. Phenyl is the preferred arylgroup.

“Heterocycle” means a fully or partially saturated ring containing atleast one heteroatom selected from N, S and O, where the ring has from 3to 10 atoms, unless otherwise defined.

“Heteroaryl” (and “heteroarylene”) means an aromatic ring containing atleast one ring heteroatom selected from N, O and S (including SO andSO₂), where the ring contains 5-6 atoms. Examples of heteroaryl includepyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl,oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, and pyrazinyl.Heteroaryl and aromatic rings can be fused together to form bicyclic ortricyclic ring systems, as for example benzisoxazolyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl (includingS-oxide and dioxide), quinolyl, indolyl, isoquinolyl, dibenzofuran andthe like.

“Halogen” includes fluorine, chlorine, bromine and iodine. Fluorine isgenerally the most preferred halogen substituent on an alkyl group.

“Me” and “Et” represent methyl and ethyl respectively.

The term “administration of” or “administering” a compound meansproviding a compound of this invention or a prodrug of a compound ofthis invention to a patient in need of treatment.

The “patient” to whom the compounds of this invention can beadministered may be selected from mammals, including primates, such asmonkeys and apes; bovines, such as cows; equines, such as horses;canines, such as dogs; felines, such as cats; ovines, such as goats andsheep; and rodents, such as mice, rats, and guinea pigs. Patients mayalso include non-mammalian species, such as chickens and other birds.The preferred patient is a human.

To treat, as a disease or condition, means to deal with the disease orcondition in a specified manner.

Amelioration of a disease or condition means improving the disease orcondition or making it better.

“Metabolic Syndrome” is defined in the Third Report of the NationalCholesterol Education Program Expert Panel on Detection, Evaluation andTreatment of High Blood Cholesterol In Adults (ATP-III). E. S. Ford etal., JAMA, vol. 287 (3), Jan. 16, 2002, pp 356-359. Briefly, a person isdefined as having metabolic syndrome if the person has three or more ofthe the following symptoms: abdominal obesity, hypertriglyceridemia, lowHDL cholesterol, high blood pressure, and high fasting plasma glucose.The criteria for these are defined in ATP-III.

The term “composition,” as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier.

Optical Isomers—Diastereomers—Geometric Isomers—Tautomers

Compounds of Formula I may contain one or more asymmetric centers. Thecompounds can thus occur as racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. The presentinvention is meant to comprehend all such isomeric forms of thecompounds of Formula I.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist with different pointsof attachment of hydrogen coupled with double bond shifts, referred toas tautomers. An example is a carbonyl (e.g. a ketone) and its enolform, often known as keto-enol tautomers. The individual tautomers aswell as mixtures thereof are encompassed with compounds of Formula I.

If desired, racemic mixtures of compounds of Formula I may be separatedby means of classical resolution through fractional crystallization ofsalts formed with enantiomerically pure acids or bases. Otherdiasteromeric derivatives can be formed by the coupling of a racemicmixture of the compounds of Formula I to an enantiomerically purecompound. Such diastereomeric mixture may be separated by standardchromatographic methods or recrystallization protocols. Thesediasteromeric derivatives may then be converted to the pure enantiomersof the compounds of Formula I by cleavage of the added chiral residue.The racemic mixture of the compounds of Formula I can also be separateddirectly by chromatographic methods utilizing chiral stationary phases,of which many examples are known in the literature.

Alternatively, any enantiomer of a compound of the general Formula I maybe obtained by stereoselective synthesis using optically pure startingmaterials or reagents of known configuration.

Compounds of Formula I that have more than one asymmetric center andthat occur as diasteromeric mixtures can similarly be separated intoindividual diastereomers by standard methods, and these can be separatedto individual enantiomers as described above.

Salts

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. For thecarboxylic acid compounds of Formula I, salts derived from inorganicbases include aluminum, ammonium, calcium, copper, ferric, ferrous,lithium, magnesium, manganous, manganic, potassium, sodium, and zincsalts and the like. Particularly preferred are the ammonium, calcium,magnesium, potassium, and sodium salts. Salts in the solid form mayexist in more than one crystal structure, and may also be in the form ofhydrates. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, substituted amines including naturally occurring substitutedamines, cyclic amines, and basic ion exchange resins, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

For compounds that are basic, salts may be prepared frompharmaceutically acceptable non-toxic acids, including inorganic andorganic acids. Such acids include acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.Particularly preferred are citric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric, and tartaric acids.

It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Metabolites—Prodrugs

Prodrugs are compounds that are converted to the claimed compounds asthey are being administered to a patient or after they have beenadministered to a patient. The prodrugs are compounds of this invention,and the active metabolites of the prodrugs, where the metabolites haveFormula I, are also compounds of the invention. A non-limiting exampleof a prodrug of the carboxylic acids of this invention is an ester ofthe carboxylic acid, as for example a C₁ to C₆ ester, or an ester whichhas functionality that makes it more easily hydrolyzed afteradministration to a patient.

Examples of prodrugs of this class of compounds may be described ascompounds having Formula Ia, where G is a group that is easily removedunder

physiological conditions during or after administration to a mammalianpatient to yield the free carboxylic acid or carboxylate salt thereof,where G has been converted to OH, or the carboxylate salt thereof. Theother substituents in Formula Ia are as previously defined for FormulaI.

Examples of prodrugs of Formula Ia include compounds in which G isselected from the group consisting of —OR^(a), —OCH₂OR^(a),—OCH(CH₃)OR^(a), —OCH₂OC(O)R^(a), —OCH(CH₃)OC(O)R^(a), —OCH₂OC(O)OR^(a),—OCH(CH₃)OC(O)OR^(a), and —NR^(b)R^(b), where each R^(a) isindependently selected from C₁₋₆ alkyl which is optionally substitutedwith one or two groups selected from —CO₂H, —CONH₂, —NH₂, —OH, —OAc,—NHAc, and phenyl; and wherein each R^(b) is independently selected fromH and R^(a).

Utilities

Compounds of the present invention are potent agonists of the peroxisomeproliferator activated receptor subtypes, particularly PPARα, withlittle or no activity with respect to PPARγ or PPARδ. Compounds of thepresent invention are thus selective and potent agonists of the subtypePPARα. Compounds of the present invention are useful in treating,controlling or ameliorating diseases, disorders and conditions, wherethe treatment, control or amelioration is effected by the activation ofthe PPARα subtype.

An important aspect of this invention is that it provides a method forthe treatment, or amelioration of various lipid disorders, includingdyslipidemia, hypercholesterolemia, hyperlipidemia,hypertriglyceridemia, low HDL levels, high LDL levels, andatherosclerosis and its sequelae, which comprises administering to apatient in need of such treatment a therapeutically effective amount ofa compound having formula I.

The compounds as defined herein may be used in treating one or more ofthe following diseases or conditions in a mammalian or human patient inneed of treatment, where the treatment comprises the administration of atherapeutically effective amount of a compound of Formula I to thepatient in need of treatment:

-   -   (1) lipid disorders;    -   (2) hyperlipidemia;    -   (3) low HDL-cholesterol;    -   (4) high LDL-cholesterol;    -   (5) hypercholesterolemia;    -   (6) hypertriglyceridemia;    -   (7) dyslipidemia, including high LDL cholesterol and low HDL        cholesterol; and    -   (8) atherosclerosis, including sequelae of atherosclerosis        (angina, claudication, heart attack, stroke, etc.).

More generally, compounds having Formula I may be used to treat orameliorate one or more of the following diseases, disorders andconditions: (1) lipid disorders, (2) dyslipidemia, (3) hyperlipidemia,(4) hypertriglyceridemia, (5) hypercholesterolemia, (6) low HDL levels,(7) high LDL levels, (8) atherosclerosis and its sequelae, (9) obesity,including abdominal obesity (10) vascular restenosis, (11) retinopathy,(12) non-insulin dependent diabetes mellitus (NIDDM), (13)hyperglycemia, (14) impaired glucose tolerance, (15) insulin resistance,(16) irritable bowel syndrome, (17) inflammatory bowel disease,including Crohn's disease and ulcerative colitis, (18) pancreatitis,(19) other inflammatory conditions, (20) neurodegenerative disease, (21)Alzheimer's disease, (22) psoriasis, (23) acne vulgaris, (24) other skindiseases and dermatological conditions modulated by PPAR, (25) highblood pressure, (26) cachexia, and (27) the metabolic syndrome,sometimes known as Syndrome X.

The compounds may also be useful in the treatment of (1) neoplasticconditions, (2) adipose cell tumors, (3) adipose cell carcinomas, suchas liposarcoma, (4) prostate cancer and other cancers, includinggastric, breast, bladder and colon cancers, and (5) angiogenesis.

Other conditons which may be treated with the compounds of thisinvention include ovarian hyperandrogenism (polycystic ovariansyndrome), cachexia, and other disorders where insulin resistance is acomponent.

The present invention is further directed to a method for themanufacture of a medicament that is useful for the treatment or controlof a disease or condition that is treated by the administration of aPPARα agonist, wherein the method comprises combining an effectiveamount of the compound of Formula I with a pharmaceutically acceptablecarrier or diluent.

Another aspect of the invention provides a method of treating cachexia.PPARα is known to be necessary for an appropriate energy sparingresponse to starvation, and inappropriate metabolism and energyutilization is clearly responsible for the wasting of cachexia. Thecompounds of this invention may therefore be useful in the treatment ofcachexia.

In another aspect, the invention provides a method of treatinginflammatory conditions, including inflammatory bowel disease, Crohn'sdisease, and ulcerative colitis, by administration of an effectiveamount of a PPARα agonist of Formula I. Additional inflammatory diseasesthat may be treated with the instant invention include gout, rheumatoidarthritis, osteoarthritis, multiple sclerosis, asthma, ARDS, psoriasis,vasculitis, ischemia/reperfusion injury, and related diseases.

Another aspect of the invention provides a method of treating a varietyof skin diseases and dermatological conditions that are modulated byPPARα agonists by administering an effective amount of a compound ofFormula I to a mammalian or human patient in need of such treatment.These diseases and conditions include psoriasis and acne vulgaris.Examples of other skin diseases and dermatological disorders that may betreated include eczema; lupus associated skin lesions; dermatitides suchas seborrheic dermatitis and solar dermatitis; keratoses such asseborrheic keratosis, senile keratosis, actinic keratosis, photo-inducedkeratosis, and keratosis follicularis; keloids and prophylaxis againstkeloid formation, warts including verruca, condyloma, or condylomaaccuminatum, and human papilloma viral (HPV) infections such as venerealwarts, viral warts, molluscum contagiosum, leukoplakia, lichen planus,keratitis, skin cancer such as basal cell carcinoma, cutaneous T celllymphoma and localized benign epidermal tumors (keratoderma, epidermalnaevi).

Administration and Dose Ranges

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like. Preferably compounds ofFormula I are administered orally.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.Such dosage may be ascertained readily by a person skilled in the art.

When treating hypertriglyceridemia, hypercholesterolemia, dyslipidemia,hyperlipidemia, and other diseases for which compounds of Formula I areindicated, generally satisfactory results are obtained when thecompounds of the present invention are administered at a daily dosage offrom about 0.1 milligram to about 100 milligram per kilogram of animalbody weight, preferably given as a single daily dose or in divided dosestwo to six times a day, or in sustained release form. For most largemammals, the total daily dosage is from about 1.0 milligrams to about1000 milligrams, preferably from about 1 milligrams to about 50milligrams. In the case of a 70 kg adult human, the total daily dosewill generally be from about 1 milligram to about 350 milligrams. Thisdosage regimen will vary depending on the specific compound and also thepatient. The dosage may be adjusted within the ranges recited above oreven outside those ranges in order to provide the optimal therapeuticresponse.

Pharmaceutical Compositions

Another aspect of the present invention provides pharmaceuticalcompositions which comprise a compound of Formula I and apharmaceutically acceptable carrier. The pharmaceutical compositions ofthe present invention comprise a compound of Formula I or apharmaceutically acceptable salt or prodrug thereof as an activeingredient, as well as a pharmaceutically acceptable carrier andoptionally other therapeutic ingredients. More typically, a selectedcompound of Formula I, or a pharmaceutically acceptable salt thereof,will be the only active ingredient in a composition. The term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids including inorganicbases or acids and organic bases or acids.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

In practical use, the compounds of Formula I can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, hard and soft capsules and tablets, with the solidoral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe coated by standard aqueous or nonaqueous techniques. Suchcompositions and preparations should contain at least 0.1 percent ofactive compound. The percentage of active compound in these compositionsmay, of course, be varied and may conveniently be between about 2percent to about 60 percent of the weight of the unit. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage will be obtained. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Compounds of formula I may also be administered parenterally. Solutionsor suspensions of these active compounds can be prepared in watersuitably mixed with a surfactant such as hydroxy-propylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g. glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Combination Therapy

The compounds of this invention may be used in combination with otherdrugs that may also have utility in the treatment or amelioration of thediseases or conditions for which compounds of Formula I are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefor, contemporaneously or sequentially with a compound ofFormula I. When a compound of Formula I is used contemporaneously withone or more other drugs, a pharmaceutical composition in unit dosageform containing such other drugs and the compound of Formula I ispreferred. However, the combination therapy also includes therapies inwhich the compound of Formula I and one or more other drugs areadministered on different overlapping schedules. It is also contemplatedthat when used in combination with one or more other active ingredients,the compound of the present invention and the other active ingredientsmay be used in lower doses than when each is used singly. Accordingly,the pharmaceutical compositions of the present invention include thosethat contain one or more other active ingredients, in addition to acompound of Formula I.

For example, the compounds of Formula I may be administered incombination with one or more other lipid lowering drugs, including (1) acholesterol biosynthesis inhibitor, including but not limited to, anHMG-CoA reductase inhibitor, such as lovastatin, simvastatin,pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin,rosuvastatin, and ZD-4522; (2) a cholesterol absorption inhibitor (forexample a stanol ester, a sterol glycoside such as tiqueside, or anazetidinone such as ezetimibe); (3) an ACAT inhibitor (such asavasimibe), (4) niacin; (5) a bile acid sequestrant; (6) a microsomaltriglyceride transport inhibitor; (7) a bile acid reuptake inhibitor;and (8) a PPARα/γ agonist, such as KRP-297. These combination treatmentsare expected to be particularly effective for the treatment or controlof one or more lipid disorders or conditions selected from dyslipidemia,hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, low HDLlevels, high LDL levels, and atherosclerosis and its sequelae. Thecombination therapy may make it possible to achieve therapeutic controlusing a reduced amount of one or both active ingredients and/or toachieve better lipid control than would be expected based on the controlthat is achieved when either of the compounds is used alone. Thecombination therapy may make it possible to achieve therapeutic controlof one or more lipid disorders and diabetes. Preferred combinationsinclude a compound of Claim I and one or more other compounds selectedfrom a cholesterol absorption inhibitor, such as ezetimibe, a statin(e.g. simvastatin, atorvastatin, or rosuvastatin), an ACAT inhibitor, oranother PPARα agonist, such as fenofibrate or another fibrate. Highlypreferred combinations include combinations consisting essentially of acompound of this invention with a cholesterol absorption inhibitor(ezetimibe), or a compound of this invention with a statin (egsimvastatin), or a compound of this invention with both a statin and acholesterol asorption inhibitor.

More generally, examples of therapeutic classes of compounds that may beadministered in combination with a compound of Formula I, eitherseparately or in the same pharmaceutical composition, include, but arenot limited to:

-   -   (a) insulin sensitizers;    -   (b) antidiabetic compounds;    -   (c) cholesterol lowering agents;    -   (d) antiobesity compounds;    -   (e) anti-inflammatory compounds; and    -   (f) antihypertensives.

Examples of classes of compounds that may be administered in combinationwith compounds having Formula I include:

-   -   (a) PPARγ agonists and partial agonists, such as the glitazones        (e.g. troglitazone, pioglitazone, englitazone, MCC-555,        rosiglitazone, and the like);    -   (b) PPARα/γ dual agonists, such as KRP-297;    -   (c) other PPARα agonists, such as fenofibric acid derivatives,        including gemfibrizol, clofibrate, fenofibrate, and bezafibrate,    -   (d) PPARδ agonists such as those disclosed in WO97/28149;    -   (e) biguanides, such as metformin and phenformin;    -   (f) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;    -   (g) dipeptidyl peptidase IV (DP-IV) inhibitors;    -   (h) insulin or insulin mimetics;    -   (i) sulfonylureas, such as tolbutamide and glipizide, or related        materials;    -   (j) α-glucosidase inhibitors (such as acarbose);    -   (k) glucagon receptor antagonists;    -   (l) glycogen phosphorylase inhibitors;    -   (m) 11-Beta-HSD type 1 enzyme inhibitors;    -   (n) 11-Beta-HSD type 1 receptor antagonists;    -   (o) exendin-4, exendin-3, GLP-1, GLP-1 mimetics, and GLP-1        receptor agonists, such as those disclosed in WO00/42026 and        WO00/59887;    -   (p) GIP, GIP mimetics such as those disclosed in WO00/58360, and        GIP receptor agonists;    -   (q) PACAP, PACAP mimetics, and PACAP receptor 3 agonists such as        those disclosed in WO 01/23420;    -   (r) HMG-CoA reductase inhibitors (lovastatin, simvastatin,        pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin,        rosuvastatin, ZD-4522, and other statins);    -   (s) Bile acid sequestrants (cholestyramine, colestipol, and        dialkylaminoalkyl derivatives of a cross-linked dextran);    -   (t) nicotinyl alcohol, nicotinic acid or a salt thereof;    -   (u) ezetimibe and other inhibitors of cholesterol absorption;    -   (v) acyl CoA:cholesterol acyltransferase inhibitors (ACAT        inhibitors); such as for example avasimibe;    -   (w) phenolic anti-oxidants, such as probucol;    -   (x) ileal bile acid transporter inhibitors;    -   (y) agents intended for use in the treatment of inflammatory        conditions such as aspirin, non-steroidal anti-inflammatory        drugs, glucocorticoids, azulfidine, and cyclooxygenase 2        selective inhibitors;    -   (z) antiobesity compounds such as fenfluramine, dexfenfluramine,        phentermine, sibutramine, orlistat, neuropeptide Y5 inhibitors,        and β₃ adrenergic receptor agonists;    -   (aa) thyroid hormone mimetics;    -   (bb) LXR agonists;    -   (cc) FXR agonists;    -   (dd) PLTP inhibitors;    -   (ee) CETP inhibitors;    -   (ff) glucocorticoids; and    -   (gg) TNF sequestrants.

The above combinations will generally include combinations of onecompound of the present invention with one other active compound.However, it is contemplated that combinations may also include more thantwo active ingredients, selected from one or more compounds of thepresent invention and one or more other active compounds listed above.Non-limiting examples include combinations of one or more compoundshaving Formula I with two or more active compounds selected from insulinsensitizers; antidiabetic compounds; cholesterol lowering agents;antiobesity compounds; anti-inflammatory compounds; andantihypertensives.

Examples of combinations that may be appropriate for patients havingType 2 diabetes accompanied by dyslipidemia include one or morecompounds having Formula I and one or more compounds selected fromanti-diabetic compounds, including biguanides, sulfonylureas, otherPPARγ agonists, PTP-1B inhibitors, DP-IV inhibitors, insulin, andanti-obesity compounds.

Biological Assays

A) PPAR Binding Assays

For preparation of recombinant human PPARγ, PPARδ, and PPARα: HumanPPARγ₂, human PPARδ and human PPARα were expressed as gst-fusionproteins in E. coli. The full length human cDNA for PPARγ₂ was subclonedinto the pGEX-2T expression vector (Pharmacia). The full length humancDNAs for PPARδ and PPARα were subcloned into the pGEX-KT expressionvector (Pharmacia). E. coli containing the respective plasmids werepropagated, induced, and harvested by centrifugation. The resuspendedpellet was broken in a French press and debris was removed bycentrifugation at 12,000×g. Recombinant human PPAR receptors werepurified by affinity chromatography on glutathione sepharose. Afterapplication to the column, and one wash, receptor was eluted withglutathione. Glycerol (10%) was added to stabilize the receptor andaliquots were stored at −80° C.

For binding to PPARγ, an aliquot of receptor was incubated in TEGM (10mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 μL/100 mL β-mercaptoethanol,10 mM Na molybdate, 1 mM dithiothreitol, 5 μg/m. aprotinin, 2 μg/mLleupeptin, 2 μg/mL benzamidine and 0.5 mM PMSF) containing 0.1% non-fatdry milk and 10 nM [³H₂] AD5075, (21 Ci/mmole), ±test compound asdescribed in Berger et al (Novel peroxisome proliferator-activatedreceptor (PPARγ) and PPARδ ligands produce distinct biological effects.J. Biol. Chem. (1999), 274: 6718-6725.) Assays were incubated for ˜16 hrat 4° C. in a final volume of 150 μL. Unbound ligand was removed byincubation with 100 μL dextran/gelatin-coated charcoal, on ice, for ˜10min. After centrifugation at 3000 rpm for 10 min at 4° C., 50 μL of thesupernatant fraction was counted in a Topcount.

For binding to PPARδ, an aliquot of receptor was incubated in TEGM (10mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 μL/100 mL β-mercaptoethanol,10 mM Na molybdate, 1 mM dithiothreitol, 5 μg/mL aprotinin, 2 μg/mLleupeptin, 2 μg/mL benzamide and 0.5 mM PMSF) containing 0.1% non-fatdry milk and 2.5 nM [³H₂]L-783483, (17 Ci/mmole), ±test compound asdescribed in Berger et al (Novel peroxisome proliferator-activatedreceptors (PPARγ) and PPARδ ligands produce distinct biological effects.1999 J Biol Chem 274: 6718-6725). (L-783483 is3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-benz-[4,5]-isoxazoloxy)propylthio)phenylaceticacid, Ex. 20 in WO 97/28137). Assays were incubated for ˜16 hr at 4° C.in a final volume of 150 μL. Unbound ligand was removed by incubationwith 100 μL dextran/gelatin-coated charcoal, on ice, for ˜10 min. Aftercentrifugation at 3000 rpm for 10 min at 4° C., 50 μL of the supernatantfraction was counted in a Topcount.

For binding to PPARα, an aliquot of receptor was incubated in TEGM (10mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 μL/100 mL β-mercaptoethanol,10 mM Na molybdate, 1 mM dithiothreitol, 5 μg/mL aprotinin, 2 μg/mLleupeptin, 2 μg/mL benzamide and 0.5 mM PMSF) containing 0.1% non-fatdry milk and 5.0 nM[³H₂](3-(4-(3-phenyl-7-propyl-6-benz-[4,5]-isoxazoloxy)butyloxy))phenylaceticacid (34 Ci/mmole), ±test compound. This is a tritium labelled variantof Ex.62 in WO 97/28137. Assays were incubated for ˜16 hr at 4° C. in afinal volume of 150 μL. Unbound ligand was removed by incubation with100 μL dextran/gelatin-coated charcoal, on ice, for ˜10 min. Aftercentrifugation at 3000 rpm for 10 min at 4° C., 50 μL of the supernatantfraction was counted in a Topcount.

B). Gal-4 hPPAR Transactivation Assays

The chimeric receptor expression constructs, pcDNA3-hPPARγ/GAL4,pcDNA3-hPPARδ/GAL4, pcDNA3-hPPARα/GAL4 were prepared by inserting theyeast GAL4 transcription factor DBD adjacent to the ligand bindingdomains (LBDs) of hPPARγ, hPPARδ, hPPARα, respectively. The reporterconstruct, pUAS(5X)-tk-luc was generated by inserting 5 copies of theGAL4 response element upstream of the herpes virus minimal thymidinekinase promoter and the luciferase reporter gene. pCMV-lacZ contains thegalactosidase Z gene under the regulation of the cytomegaloviruspromoter. COS-1 cells were seeded at 12×10³ cells/well in 96 well cellculture plates in high glucose Dulbecco's modified Eagle medium (DMEM)containing 10% charcoal stripped fetal calf serum (Gemini Bio-Products,Calabasas, Calif.), nonessential amino acids, 100 units/ml Penicillin Gand 100 mg/ml Streptomycin sulfate at 37° C. in a humidified atmosphereof 10% CO₂. After 24 h, transfections were performed with Lipofectamine(GIBCO BRL, Gaithersburg, Md.) according to the instructions of themanufacturer. Briefly, transfection mixes for each well contained 0.48μl of Lipofectamine, 0.00075 μg of pcDNA3-PPAR/GAL4 expression vector,0.045 μg of pUAS(5X)-tk-luc reporter vector and 0.0002 μg of pCMV-lacZas an internal control for transactivation efficiency. Cells wereincubated in the transfection mixture for 5 h at 37° C. in an atmosphereof 10% CO₂. The cells were then incubated for ˜48 h in fresh highglucose DMEM containing 5% charcoal stripped fetal calf serum,nonessential amino acids, 100 units/ml Penicillin G and 100 mg/mlStreptomycin sulfate ±increasing concentrations of test compound. Sincethe compounds were solubilized in DMSO, control cells were incubatedwith equivalent concentrations of DMSO; final DMSO concentrations were≦0.1%, a concentration which was shown not to effect transactivationactivity. Cell lysates were produced using Reporter Lysis Buffer(Promega, Madison, Wis.) according to the manufacturer's instructions.Luciferase activity in cell extracts was determined using LuciferaseAssay Buffer (Promega, Madison, Wis.) in an ML3000 luminometer (DynatechLaboratories, Chantilly, Va.). β-galactosidase activity was determinedusing β-D-galactopyranoside (Calbiochem, San Diego, Calif.).

C. In Vivo Studies

Male db/db mice (10-11 week old C57B1/KFJ, Jackson Labs, Bar Harbor,Me.) were housed 5/cage and allowed ad lib. access to ground Purinarodent chow and water. The animals, and their food, were weighed every 2days and were dosed daily by gavage with vehicle (0.5%carboxymethylcellulose) ±test compound at the indicated dose. Drugsuspensions were prepared daily. Plasma glucose, and triglycerideconcentrations were determined from blood obtained by tail bleeds at 3-5day intervals during the study period. Glucose, and triglyceride,determinations were performed on a Boehringer Mannheim Hitachi 911automatic analyzer (Boehringer Mannheim, Indianapolis, Ind.) usingheparinized plasma diluted 1:6 (v/v) with normal saline. Lean animalswere age-matched heterozygous mice maintained in the same manner.

Male Golden Syrian hamsters weighing ˜150 g are used to measure lipidmodulation effects of test compounds. Hamsters are housed in boxes (5per box), are fed a normal rodent chow diet, and are given free accessto water. Compounds are suspended in 0.5% methylcellulose and gavageddaily to the hamsters for 9 days (10 hamsters per group). On the morningof the 10^(th) day, the hamsters are euthanized with carbon dioxide, andblood samples are obtained via heart puncture. Serum levels of totalcholesterol and triglycerides determined.

Mature male beagle dogs, weighing ˜15 kg on average, are used to measurethe lipid modulation effects of test compounds. Dogs are housedindividually, are fed a cholesterol-free chow diet, and are given freeaccess to water. Prior to the start of experiments, samples are takenweekly from the jugular vein and the serum cholesterol levels aredetermined. To test the effects of compounds on serum cholesterol,compounds are suspended in 0.5% methylcellulose and gavaged daily to thedogs for 2 weeks (5 dogs per group). Blood samples are taken during andafter the dosing period, and serum levels of total cholesterol andtriglycerides are determined. TABLE OF COMPOUNDS The table belowillustrates compounds that were synthesized in accordance with thepresent invention. Detailed syntheses are provided in the Examples.Example 1

Example 2

Example 3

Example 4

Example 5

Example 6

Example 7

Example 8

Example 9

Synthetic Methods

The process for making the compounds of the instant invention isgenerally depicted in Scheme 1 below.

Note that the numbering of substituent groups used in the structures inScheme I is different from the numbering in the generic description ofthe invention.

The final compounds are assembled by the base-catalyzed coupling ofchromen/chromanol precursors or the thiol analogs of these compounds(III) with precursors (II). Alternatively, these compounds are alsoavailable by coupling of precursors (I) and (IV). Coupling is carriedout in the presence of an inorganic base (e.g. cesium carbonate) in DMF.The coupling can also be carried out under Mitsunobu reactionconditions. Lv(₁) and Lv(₂) are leaving groups well-known in the art,and preferably are independently selected from halogen, preferablyiodine or bromine, or sulfonate such as methanesulfonate, or hydroxyl inthe case of Mitsunobu reaction conditions. The desired carboxylic acidsVI may be synthesized by ester hydrolysis of the compounds havingformula V under aqueous basic (e.g. aq. KOH) conditions.

EXAMPLES

The following Examples are provided to illustrate the invention,including methods of making the compounds of the invention, and are notto be construed as limiting the invention in any manner. The scope ofthe invention is defined only by the appended claims.

Example 12-(4-(3-((6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propoxy)phenoxy)-2-methylbutanoicacid

Step A: Methyl 2-(4-(benzyloxy)phenoxy)butanoate

A mixture of 4-benzyloxyphenol (30 g, 0.15 mol), cesium carbonate (58.6g, 0.18 mol) and methyl 2-bromobutanoate (40.7 g, 0.22 mol) in CH₃CN(350 mL) was kept at reflux for 20 hr. After cooling, the mixture wasfiltered and concentrated under reduced pressure and chromatographedover silica gel using AcOEt/hexanes to give the title compound 41.0 g(91%).

¹H-N (400 MHz, CDCl₃): δ 7.45-7.31 (m, 7H), 6.9 (d, 2H, J=9.2 Hz), 6.85(d, 2H, J=9.2 Hz), 5.02 (s 2H), 4.45 (t, 1H, J=6.3 Hz), 3.76 (s, 3H),1.98 (dq, 2H, J=7.4,6.3 Hz), 1.08 (t, 3H, J=7.4 Hz).

Step B: Methyl-(4-(benzyloxy)phenoxy)-2-methylbutanoate

To a 200 mL THF solution of methyl 2-(4-(benzyloxy)phenoxy)butanoate (30g, 0.1 mol) was added at −78° C., a solution of lithium diisopropylamide(65 mL of 2 mol solution). After the addition was over, the resultingmixture was stirred at −78° C. for 30 min. To this was then added methyliodide (15 mL) and stirring continued for 4 h during which thetemperature was gradually allowed to rise. After quenching the reactionwith sat.NH₄Cl aq, the layers were separated and the aqueous layer wasextracted with AcOEt and the combined organic phase washed with water,brine, dried over anhydrous Na₂SO₄ and concentrated to furnish thedesired product (32 g). This product was used as such for the next step.

¹H-NMR (400 MHz, CDCl₃): δ 7.45-7.19 (m, 7H), 6.86 (d, 2H, J=9.3 Hz),6.84 (d, 2H, J=9.2 Hz), 5.02 (s 2H), 3.79 (s, 3H), 1.97 (m, 2H), 1.45(s, 3H), 0.99 (t, 3H, J=7.4 Hz).

Step C: Methyl 2-(4-hydroxyphenoxy)-2-methylbutanoate

A solution of methyl-(4-(benzyloxy)phenoxy)-2-methylbutanoate (32 g) in100 mL MeOH was hydrogenated using 10% Pd/C at 40 psi. The mixture wasfiltered through a pad of celite to remove the catalyst. The filtratewas concentrated to afford thick oily residue (21 g, quantitative).

¹H-NMR (400 MHz, CDCl₃): δ 6.78 (d, 2H, J=9.0 Hz), 6.72 (d, 2H, J=9.0Hz), 4.08 (s 1H), 3.79 (s, 3H), 1.98 (m, 2H), 1.43 (s, 3H), 0.99 (t, 3H,J=7.4 Hz).

Step D: Methyl 2-(4-(3-hydroxypropoxy)phenoxy)-2-methylbutanoate

To a solution of methyl 2-(4-hydroxyphenoxy)-2-methylbutanoate ( 5 g,22.32 mmol) in 30 mL DMF was added cesium carbonate (8.7 g, 26.7 mmol)followed by benzyl 3-bromopropyl ether (7.7 g, 33.6 mmol). The solutionwas stirred at 45° C. for 24 hr, cooled and poured over water.Extraction with AcOEt followed by washing the extracts with water,drying over anhydrous Na₂SO₄ and concentrating under reduced pressuregave the crude residue. Purification over silica gel using AcOEt/hexanesfurnished the desired alkylated derivative (8.25 g). This product wastaken up in MeOH (75 mL) and hydrogenated over 10% Pd/C at 40 psi toprovide methyl 2-(4-(3-hydroxypropoxy)phenoxy)-2-methylbutanoate (6.23g, quantitative).

¹H-NMR (400 MHz, CDCl₃): δ 6.82 (d, 2H, J=9.4 Hz), 6.78 (d, 2H, J=9.2Hz), 4.08 (t, 2H, J=6.1 Hz), 3.87 (t, 2H, J=6 Hz), 3.79 (s, 3H),2.06-1.92 (m, 4H), 1.44 (s, 3H), 0.99 (t, 3H, J=7.4 Hz).

Step E: 6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-ol

To a solution of 6-chloro-7-hydroxy-4-(trifluoromethyl)-2H-chromen-2-one(1.5 g, 5.68 mmol) in anhydrous THF (25 mL) was added at 0° C. asolution of methyl magnesium chloride in THF (9.48 mL of 3 molsolution). After stirring at 0° C. for 1 h, the reaction was quenchedwith sat.NH₄Cl aq. The organic layer was separated, washed with water,dried over anhydrous Na₂SO₄ and concentrated to provide the crudeproduct. This was dissolved in toluene (50 mL) and to this was addedp-toluenesulfonic acid (40 mg) and the solution was kept at reflux for 1h with the azeotropic removal of water using Dean-Stark apparatus. Thesolution washed once with water, dried over anhydrous Na₂SO₄ andconcentrated to give brownish residue which was subjected topurification over silica gel using AcOEt/hexanes to provide the desiredproduct (1.3 g, 83%).

¹H-NMR (400 MHz, CDCl₃): δ 6.56 (s, 1H), 6.09 (s, 1H), 5.63 (s, 11),1.48 (s, 6H).

Step F: Methyl2-(4-(3-((6-chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propoxy)phenoxy)-2-methylbutanoate

To a solution of6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-ol (0.66 g, 2.95mmol), methyl 2-(4-(3-hydroxypropoxy)phenoxy)-2-methylbutanoate (1.0 g,2.97 mmol) and triphenylphosphine (0.85 g, 3.24 mmol) in 25 mL THF isadded diethyl azodicarboxylate (0.56 g, 3.21 mmol)(slight exotherm) andthe reaction mixture is stirred at ambient temperature overnight (16 h).After concentrating under reduced pressure, the residue obtained ischromatographed over silica gel to provide methyl2-(4-(3-((6-chloro-2,2-dimethyl4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propoxy)phenoxy)-2-methylbutanoate(0.99 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.3(s, 1H), 6.81 (q, 4H, J=3 Hz), 6.82 (d,2H, J=7.5 Hz), 6.51 (s, 1H), 6.06 (s, 1H), 4.19 (t, 2H, J=6.1 Hz), 4.14(t, 2H, J=6.1 Hz), 3.79 (s, 3H), 2.29 (m, 2H), 1.95 (m, 2H), 1.47 (s,6H), 1.43 (s, 3H), 0.99 (t, 3H, J=7.5 Hz).

Step G:2-(4-(3-((6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propoxy)phenoxy)-2-methylbutanoicacid

The above ester is dissolved in MeOH (10 mL) and treated with 50% NaOHaq (2 mL) at room temperature overnight (15 h), concentrated andacidified with 2N HCl aq. The aqueous solution is extracted with AcOEt,dried over anhydrous Na₂SO₄ and concentrated to give 0.73 g of the titlecompound.

¹H-NMR (400 MHz, CDCl₃): δ 7.3(s, 1H), 6.92 (d, 2H, J=9.2 Hz), 6.84 (d,2H, J=9.0 Hz), 6.51 (s, 1H), 6.06 (s, 1H), 4.2 (t, 2H, J=6.0 Hz), 4.17(t, 2H, J=6.0) 2.31(m, 2H), 1.99-1.8 (m, 2H), 1.47 (s, 6H), 1.06(t, 3H,J=7.4 Hz). MS m/e=529 (M⁺+H).

Example 2(2R)-2-(4-(3-((6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propoxy)phenoxy)-2-methylbutanoicacid

Step A:

1) Resolution of the racemic methyl2-(4-hydroxyphenoxy)-2-methylbutanoate

The racemic methyl 2-(4-hydroxyphenoxy)-2-methylbutanoate (144 g)prepared according to Example 1, Steps A-C was resolved on a preparatoryscale using Chiaracel OJ (3 kg-gel) packed in a 6″×22″ column. Elutionwith 30% EtOH-70% heptane gave the faster eluting (R) isomer (67.6 g)and slower eluting (S) isomer (49.5 g). On an analytical Chiracel OJcolumn (4.6 mm×250 mm, 20% EtOH-80% heptane, flow rate 1 ml/min, (+) CDdeflection at 254 nm), the faster eluting (R) isomer had a RT=13.31 minand the slower eluting (S) isomer had a RT=18.86 min.

2) Determination of Absolute Stereochemistry

The slower moving isomer obtained as described above was converted to(2R)-2-phenyloxazolinone amide A. The stereochemistry at the chiralcenter of the isomer A was found to be (S) by X-ray crystallography.This means that the faster eluting isomer has (R) configuration at thechiral center.

The structure of the isomer A has been determined by single crystalX-Ray

crystallography. Crystals suitable for diffraction studies were grownfrom a mixture of acetone/water. The crystals obtained are monoclinicwith space group P2₁ and cell constants of a=10.544(2), b=5.766(3),c=15.589(2) Å, β=92.36(1)°, with V=947.0(8) Å³, and Z=2. The calculateddensity is 1.295 g cm⁻³ .

All diffraction measurements were made using monochromatized Cu Kαradiation (λ=1.54184 Å) on a Rigaku AFC5 diffractometer to a θlimit of70.35°. There are 1908 unique reflections out of 2009 measured with 1374observed at the I≧2σ(I) level. The structure was solved by directmethods and refined using full-matrix least-squares on F² using 244parameters and all unique reflections. The refinement converged withagreement statistics of R=0.063, wR=0.190, S=1.06 with (Δ/σ)max<0.01.

A computer-generated perspective view of the molecule is shown inFIG. 1. Lists of interatomic distances and angles are given in Tables 1and 2, respectively.

TABLE 1 Interatomic Distances (Å) O3—C2 1.334(8) C7—C8 1.365(9) O3—C41.424(8) C8—C9 1.389(12) O12—C2 1.188(7) C9—C10 1.360(12) O14—C131.188(8) C10—C11 1.376(10) O16—C17 1.378(7) C13—C15 1.561(9) O16—C151.428(8) C15—C25 1.517(11) O23—C20 1.376(8) C15—C27 1.537(9) O23—C241.394(13) C17—C18 1.372(10) N1—C2 1.396(8) C17—C22 1.397(10) N1—C131.409(9) C18—C19 1.382(10) N1—C5 1.480(7) C19—C20 1.375(10) C4—C51.532(10) C20—C21 1.383(11) C5—C6 1.497(8) C21—C22 1.371(9) C6—C111.385(9) C25—C26 1.510(10) C6—C7 1.413(9)

TABLE 2 Interatomic Angles (deg.) C2—O3—C4 110.8(5) O14—C13—N1 119.6(6)C17—O16—C15 122.4(5) O14—C13—C15 119.3(7) C20—O23—C24 117.9(7)N1—C13—C15 121.0(6) C2—N1—C13 126.1(5) O16—C15—C25 111.9(5) C2—N1—C5110.0(5) O16—C15—C27 102.9(5) C13—N1—C5 117.0(6) C25—C15—C27 111.1(6)O12—C2—O3 121.5(6) O16—C15—C13 107.6(5) O12—C2—N1 128.5(6) C25—C15—C13115.0(6) O3—C2—N1 109.9(5) C27—C15—C13 107.5(5) O3—C4—C5 106.4(5)C18—C17—O16 115.7(6) N1—C5—C6 113.7(4) C18—C17—C22 118.0(6) N1—C5—C4100.4(5) O16—C17—C22 126.4(6) C6—C5—C4 114.1(6) C17—C18—C19 121.0(7)C11—C6—C7 118.2(6) C20—C19—C18 120.8(7) C11—C6—C5 121.4(6) C19—C20—O23125.3(7) C7—C6—C5 120.4(6) C19—C20—C21 118.7(6) C8—C7—C6 120.3(6)O23—C20—C21 116.1(7) C7—C8—C9 120.6(8) C22—C21—C20 120.6(7) C10—C9—C8119.1(6) C21—C22—C17 120.9(7) C9—C10—C11 121.5(7) C26—C25—C15 114.8(7)C10—C11—C6 120.3(7)

Step B:(2R)-2-(4-(3-((6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propoxy)phenoxy)-2-methylbutanoicacid

As described in Example 1, Step D and F-G the title compound wasprepared using (2R)-methyl2-(4-(3-hydroxypropoxy)phenoxy)-2-methylbutanoate and6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-ol.

¹H-NMR (400 MHz, CDCl₃): δ 7.3(s, 1H), 6.92 (d, 2H, J=9.2 Hz), 6.84 (d,2H, J=9.0 Hz), 6.51 (s, 1H), 6.06 (s, 1H), 4.2 (t, 2H, J=6.0 Hz), 4.17(t, 2H, J=6.0 Hz), 2.31(m, 2H), 1.99-1.8 (m, 2H), 1.47 (s, 6H), 1.06(t,3H, J=7.4 Hz). MS m/e=529 (M⁺+H).

Example 3(2S)-2-(4-(3-((6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propoxy)phenoxy)-2-methylbutanoicacid

STEP A:3-((6-chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propan-1-ol

To a solution of6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-ol (10 g, 36.23mmol) in 150 mL DMF was added cesium carbonate (24.8 g, 76.11 mmol)followed by 3-bromo-1-propanol (7.6 g, 54.3 mmol) and the mixturestirred at ambient temperature for 24 h. Dilution with water followed byextraction with AcOE and washing the organic extracts with water, dryingover anhydrous Na₂SO₄ and finally concentrating under reduced pressuregave crude alkylated product. Purification over silica gel usingAcOEt/hexanes provided the desired3-((6-chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propan-1-ol(9.5 g, 78%).

¹H-NMR (400 MHz, CDCl₃): δ 7.32(s, 1H), 6.92 (d, 2H, J=9.2 Hz), 6.51 (s,1H), 6.07 (s, 1H), 4.19 (t, 2H, J=5.7 Hz), 3.92 (t, 2H, J=5.5 Hz),2.12(m, 2H), 1.48 (s, 6H).

STEP B: (2S)-Methyl2-(4-(3-((6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propoxy)phenoxy)-2-methylbutanoate

To a solution of3-((6-chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propan-1-ol(0.5 g, 1.48 mmol), (2S)-Methyl 2-(4-hydroxyphenoxy)-2-methylbutanoate(0.35 g, 1.56 mmol), and triphenylphosphine (0.42 g, 1.6 mmol) in THF(20 mL) was added diethyl azodicarboxylate (0.28 g, 1.6 mmol) and thesolution stirred at ambient temperature for 16 h. After concentratingunder reduced pressure, the residue thus obtained was chromatographedover silica gel using AcOEt/hexanes to furnish the desired compound(0.49 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.3(s, 1H), 6.83 (d, 2H, J=9.2 Hz), 6.81 (d,2H, J=9.2 Hz), 6.51 (s, 1H), 6.06 (s, 1H), 4.2 (t, 2H, J=6.1 Hz), 4.15(t, 2H, J=6.1 Hz), 3.79 (s,3H), 2.29(m, 2H), 1.99-1.8 (m, 2H), 1.47 (s,6H), 1.44 (s,3H), 0.99 (t, 3H, J=7.4 Hz).

STEP C:(2S)-2-(4-(3-((6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propoxy)phenoxy)-2-methylbutanoicacid

The above ester was hydrolyzed with 50% NaOH aq (1 mL) in MeOH (10 mL)to give 0.45 g of the title compound.

¹H-NMR (400 MHz, CDCl₃): δ 7.3 (s, 1H), 6.92 (d, 2H, J=9.2 Hz), 6.84 (d,2H, J=9.0 Hz), 6.51 (s, 1H), 6.06 (s, 1H), 4.2 (t, 2H, J=6.0 Hz), 4.17(t, 2H, J=6.0 Hz), 2.31(m, 2H), 1.99-1.8 (m, 2H), 1.47 (s, 6H), 1.06(t,3H, J=7.4 Hz). MS m/e=529 (M⁺+H).

Example 4(2R)-2-(4-(3-((6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)ethoxy)phenoxy)-2-methylbutanoicacid

Step A: (2R)-Methyl 2-(4-(3-hydroxyethoxy)phenoxy)-2-methylbutanoate

Using benzyl 2-bromoethylether in place of benzyl 3-bromopropyl ether,(2R)-methyl 2-(4-hydroxyphenoxy)-2-methylbutanoate was converted to thedesired (2R)-methyl 2-(4-(3-hydroxyethoxy)phenoxy)-2-methylbutanoate asdescribed in Example 1, Step D.

¹H-NMR (400 MHz, CDCl₃): δ 6.84 (d, 2H, J=9.4 Hz), 6.81 (d, 2H, J=9.4Hz), 4.04 (t, 2H, J=4.3 Hz), 3.94 (t, 2H, J=4.3 Hz), 3.79 (s, 3H), 1.96(m, 2H), 1.44 (s, 3H), 0.99 (t, 3H, J=7.6 Hz).

Step B:(2R)-2-(4-(3-((6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)ethoxy)phenoxy)-2-methylbutanoicacid

The title compound was prepared following the procedure described inExample 1, Steps F-G employing (2R)-methyl2-(4-(3-hydroxyethoxy)phenoxy)-2-methylbutanoate and6-chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-ol.

¹H-NMR (400 MHz, CDCl₃): δ 7.33(s, 1H), 6.9 (bs, 4H), 6.56 (s, 1H), 6.09(s, 1H), 4.35 (s, 4H),2.02-1.86 (m, 2H), 1.49 (s, 6H), 1.43 (s,3H), 1.08(t, 3H, J=7.3 Hz). MS m/e=515 (M⁺+H).

Example 5(2R)-2-(4-(3-((6-Chloro-2,2-dimethyl-3,4-dihydro-2H-chromen-7-yl)oxy)propoxy)phenoxy)-2-methylbutanoicacid

STEP A: 6-Chloro-2,2-dimethylchroman-7-ol

The desired 6-chloro-2,2-dimethylchroman-7-ol was synthesized from4-chlororesorcinol as follows. A mixture of 3,3-dimethylacrylic acid(7.0 g) and 4-chlororesorcinol (10 g) in Eaton's reagent (50 mL) wasstirred at ambient temperature for 16 h. At the end, the mixture waspoured over ice and the precipitate was filtered, dried and crystallizedfrom aqueous methanol to provide6-chloro-7-hydroxy-2,2-dimethyl-2,3-dihydro-4H-chomen-4-one (8.7 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.88(s, 1H), 6.58 (s, 1H), 6.01 (s, 1H), 2.69(s, 2H), 1.47 (s, 6H).

The above phenol (2.2 g) was converted to the corresponding benzyloxyderivative using benzyl bromide and the product was reduced with NaBH₄in MeOH to provide the alcohol which was then treated with conc. HCl inTHF to provide the elimination derivative. Hydrogenation of thiscompound using Pd/C catalyst in AcOEt afforded the target6-chloro-2,2-dimethylchroman-7-ol (1.55 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.0(s, 1H), 6.47 (s, 1H), 5.3 (s, 1H), 2.69(t, 2H, J=6.7 Hz), 1.78 (t, 2H, J=6.7 Hz), 1.33 (s, 6H).

STEP B:(2R)-2-(4-(3-((6-Chloro-2,2-dimethyl-3,4-dihydro-2H-chromen-7-yl)oxy)propoxy)phenoxy)-2-methylbutanoicacid

The title compound was prepared following the procedure described inExample 1, Steps F-G employing (2R)-methyl2-(4-(3-hydroxypropoxy)phenoxy)-2-methylbutanoate and6-Chloro-2,2-dimethylchroman-7-ol.

¹H-NMR (400 MHz, CDCl₃): δ 7.04(s, 1H), 6.92 (d, 2H, J=9.2 Hz), 6.84 (d,2H, J=9.0 Hz), 6.42 (s, 1H), 4.15 (m, 4H),2.69 (t, 2H, J=6.7 Hz), 2.28(m, 2H), 2-1.8 (m, 2H), 1.78 (t, 2H, J-6.9 Hz), 1.42 (s, 3H), 1.33(s,6H), 1.07 (t, 3H, J=7.4 Hz).

Example 62-(4-(3-((6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propoxy)phenoxy)-2-ethylbutanoicacid

STEP A: Methyl 2-(4-(3-hydroxypropoxy)phenoxy)-2-ethylbutanoate

Using ethyl trifluoromethanesulfonate in place of methyl iodide in thealkylation of methyl 2-(4-(benzyloxy)phenoxy)butanoate and following thesame procedure as described in Example 1, Step B-D, the target compoundmethyl 2-(4-(3-hydroxypropoxy)phenoxy)-2-ethylbutanoate was prepared.

¹H-NMR (400 MHz, CDCl₃): δ 6.83 (d, 2H, J=9.4 Hz), 6.79 (d, 2H,J=9.0Hz), 4.09 (t, 2H, J=6.0 Hz), 3.87 (t, 2H, J=5.7 Hz), 3.79 (s, 3H),2.1-1.9 (m,6H), 0.9 (t, 6H, J=7.5 Hz).

STEP B:2-(4-(3-((6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propoxy)phenoxy)-2-ethylbutanoicacid

Following the procedure described in Example 1, Step F-G the titlecompound was prepared using methyl2-(4-(3-hydroxypropoxy)phenoxy)-2-ethylbutanoate and6-chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-ol.

¹H-NMR (400 MHz, CDCl₃): δ 7.31(s, 1H), 6.95 (d, 2H, J=9.2 Hz), 6.86 (d,2H, J=9.0 Hz), 6.51 (s, 1H), 6.06 (s, 1H), 4.2-4.1 (m, 4H), 2.31(m, 2H),2.0-1.8 (m, 4H), 1.47 (s, 6H), 0.99(t, 3H, J=7.2 Hz).

Example 72-(4-(3-((6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)ethoxy)phenoxy)-2-ethylbutanoicacid

The title compound was prepared as described in Example 1, Step F-Gusing methyl 2-(4-(3-hydroxyethoxy)phenoxy)-2-ethylbutanoate and6-chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-ol.

¹H-NMR (400 MHz, CDCl₃): δ 7.33(s, 1H), 6.97 (d, 2H, J=9.1 Hz), 6.92 (d,2H, J=9.1 Hz), 6.57 (s, 1H), 6.09 (s, 1H), 4.36 (s, 4H), 2.0-1.8 (m,4H), 1.49 (s, 6H), 1.0(t, 3H, J=7.3 Hz).

Example 8(2R)-2-(4-(3-((6-Chloro-2,2-diethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propoxy)phenoxy)-2-methylbutanoicacid

STEP A: 6-Chloro-2,2-diethyl-4-(trifluoromethyl)-2H-chromen-7-ol

This compound was prepared in an analogous manner as described for thepreparation of the corresponding6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-ol, Example 1,Step E substituting ethyl magnesium chloride in place of methylmagnesium chloride.

¹H-NMR (400 MHz, CDCl₃): δ 7.25 (s, 1H), 6.57 (s, 1H), 6.01 (s, 1H),5.65 (s, 1H), 1.83-1.63 (m,4H), 0.95 (t, 6H, J=7.4 H).

Step B:2-(4-(3-((6-Chloro-2,2-diethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propoxy)phenoxy)-2-methylbutanoicacid,

Following the procedure described in Example 1, Step F-G the titlecompound was prepared using6-chloro-2,2-diethyl-4-(trifluoromethyl)-2H-chromen-7-ol and (2R)-methyl2-(4-(3-hydroxypropoxy)phenoxy)-2-methylbutanoate.

¹H-NMR (400 MHz, CDCl₃): δ 7.28 (s, 1H), 6.89 (d, 2H, J=8.2 Hz), 6.81(d, 2H, J=9.2 Hz), 6.51 (s, 1H), 5.98 (s, 1H), 4.21 (t, 2H, J=6.0 Hz),4.18 (t, 2H, J=6.0), 2.0-1.68 (m, 6H), 1.41 (s, 3H), 1.07(t, 3H, J=7.3Hz), 0.95 (t, 3H, J=7.5 Hz).

Example 9(2R)-2-(4-(3-((6-Chloro-2,2-dimethyl-4-(isopropyl)-2H-chromen-7-yl)oxy)propoxy)phenoxy)-2-methylbutanoicacid

STEP A: 6-Chloro-2,2-dimethyl-4-(isopropyl)-2H-chromen-7-ol

A mixture of 4-chlororesorcinol (2.0 g, 13.84 mmol) and ethylisobutyrylacetate (3.3 g, 20.7 mmol) in Eaton's reagent (15 mL) wasstirred at ambient temperature for 16 h, poured over ice and theprecipitated solids filtered, dried, and crystallized from aqueousmethanol to provide the desired6-chloro-2,2-dimethyl-4-(isopropyl)-2H-chromen-7-ol (2.68 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.15 (s, 1H), 6.54 (s, 1H), 5.52 (s, 1H),5.34 (s, 1H), 2.75 (m,1H), 1.4 (s, 6H), 1.15 (t, 6H, J=6.9 H).

STEP B:(2R)-2-(4-(3-((6-Chloro-2,2-dimethyl-4-(isopropyl)-2H-chromen-7-yl)oxy)propoxy)phenoxy)-2-methylbutanoicacid

The title compound was prepared following the procedure described inExample 1, Step F-G employing6-chloro-2,2-dimethyl-4-(isopropyl)-2H-chromen-7-ol.

¹H-NMR (400 MHz, CDCl₃): δ 7.2 (s, 1H), 6.9 (d, 2H, J=8.9 Hz), 6.84 (d,2H, J=8.9 Hz), 6.5 (s, 1H), 5.32 (s, 1H), 4.2-4.16 (m, 4H), 2.77 (m,1H), 2.31(m, 2H), 2.0-1.8 (m, 2H), 1.43 (s, 3H), 1.4 (s, 6H), 1.15 (d,6H, J=6.7 Hz), 1.07(t, 3H, J=7.3 Hz).

1. A compound having Formula I, or a pharmaceutically acceptable saltthereof, wherein

R¹ and R² are each C₁-C₃ alkyl, which are optionally substituted with1-5 halogens independently selected from F and Cl; R³ is selected fromthe group consisting of (a) H, and (b) C₁-C₃alkyl, which is optionallysubstituted with 1-5 halogens independently selected from F and Cl; R⁴is C₁-C₃ alkyl, which is optionally substituted with 1-5 halogensindependently selected from F and Cl; R⁵ is selected from the groupconsisting of H and C₁-C₃alkyl, which is optionally substituted with 1-5halogens independently selected from F and Cl; R⁶ is selected from H,Cl, CH₃ and CF₃; R⁷ is selected from H and C₁-C₃ alkyl, which isoptionally substituted with 1-5 halogens independently selected from Fand Cl; A and B are each selected from H, Cl, F, CH₃, and CF₃; Thedashed line connecting the ring carbon atoms attached to R⁵ and R⁷ is anoptional double bond; X and Y are independently selected from O and S;and n is an integer from 2-3.
 2. A compound according to claim 1,wherein X and Y are each O.
 3. A compound according to claim 1, whereinA, B, and R⁷ are H.
 4. A compound according to claim 1, wherein R⁵ isCF₃.
 5. A compound according to claim 1, wherein R⁵ is C₁-C₃ alkyl.
 6. Acompound according to claim 1, wherein R⁶ is selected from Cl, CH₃ andCF₃.
 7. A compound according to claim 6, wherein R⁶ is Cl.
 8. A compoundaccording to claim 1, wherein R³ and R⁴ are each independently selectedfrom CH₃, C₂H₅, and C₃H₇.
 9. A compound according to claim 1, wherein R¹and R² are each selected from CH₃ and C₂H₅.
 10. A compound according toclaim 9, wherein R¹ and R² are each CH₃.
 11. A compound according toclaim 1, wherein R¹ and R² are each independently selected from thegroup consisting of CH₃ and C₂H₅; R3 and R4 are each independentlyselected from the group consisting of CH3, C2H5, and C3H7; R⁵ is CF3; R⁶is Cl; R⁷, A, and B are H; The dashed line connecting the ring carbonatoms attached to R5 and R7 is a double bond; X and Y are O; and n is aninteger from 2-3.
 12. A compound according to claim 11, wherein R¹ andR² are each CH₃.
 13. A compound according to claim 1, having the formulashown below, or a pharmaceutically acceptable salt thereof:


14. A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 15. (canceled)
 16. A method for treating one or morelipid disorders, selected from the group consisting of dyslipidemia,hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, low HDLlevels, and high LDL levels in a patient in need of such treatment whichcomprises administering to said patient a therapeutically effectiveamount of a compound of claim
 1. 17-27. (canceled)
 28. A pharmaceuticalcomposition comprising (1) a compound according to claim 1, (2) one ormore compounds selected from the group consisting of: (a) PPARγ agonistsand partial agonists; (b) PPARα/γ dual agonists; (c) other PPARαagonists; (d) PPARδ agonists; (e) Biguanides; (f) protein tyrosinephosphatase-1B (PTP-1B) inhibitors; (g) dipeptidyl peptidase IV (DP-IV)inhibitors; (h) insulin or insulin mimetics; (i) sulfonylureas; (j)α-glucosidase inhibitors; (k) glucagon receptor antagonists; (l)glycogen phosphorylase inhibitors; (m) 11-Beta-HSD type 1 enzymeinhibitors; (n) 11-Beta-HSD type 1 receptor antagonists; (o) exendin-4,exendin-3, GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists; (p) GIP,GIP mimetics, and GIP receptor agonists; (q) PACAP, PACAP mimetics, andPACAP receptor 3 agonists; (r) HMG-CoA reductase inhibitors; (s) Bileacid sequestrants; (t) nicotinyl alcohol, nicotinic acid or a saltthereof; (u) ezetimibe and other inhibitors of cholesterol absorption;(v) acyl CoA:cholesterol acyltransferase inhibitors (ACAT inhibitors);(w) phenolic anti-oxidants; (x) ileal bile acid transporter inhibitors;(y) agents intended for use in the treatment of inflammatory conditions;(z) antiobesity compounds; (aa) thyroid hormone mimetics; (bb) LXRagonists; (cc) FXR agonists; (dd) PLTP inhibitors; (ee) CETP inhibitors;(ff) glucocorticoids; and (gg) TNF sequestrants; and (3) apharmaceutically acceptable carrier.